Familial Hemophagocytic Lymphohistiocytosis (FHLH) is almost universally fatal unless aggressively treated soon after diagnosis, and corrected with allogeneic bone marrow transplantation. All forms of FHLH likely result from genetic defects in the natural down regulating mechanisms of immune/inflammatory responses. Three autosomal recessive gene defects underlie 40-50% of primary (familial) cases worldwide: perforin (20-30%), the major immune cytotoxic protein, MUNC 13- 4 (20%), a protein involved in exocytosis of perforin-bearing cytotoxic granules during apoptosis and STX11, member of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNARE). Thus in more than half of the FHLH cases, the affected individuals have other as yet unknown genetic alterations. The classic genetic approach to identify these genes, through linkage analysis, has limitations because linkage analysis often leave investigators confronting broad genomic regions containing hundred of genes. Factors such as the impracticality of dramatically increasing the number of families tested, low allelic frequency, and the rarity of families with the disease often prevent the statistical narrowing down of these large regions to identify the involved gene. In this study, we propose a cell-biology-based approach to accelerate the dissection of FHLH susceptibility loci. Our strategy utilizes RNA interference (RNAi), the process where double-stranded RNA induces the homology-dependent degradation of cognate mRNA. The RNAi strategy will be used to identify candidate genes in lymphohistiocytosis susceptibility region on chromosome 9q21.3-22 and among genes coding for SNARE proteins essential for direct, controlled, and very rapid fusion of phospholipids membranes. PUBLIC HEALTH RELEVANCE: Familial Hemophagocytic Lymphohisticytosis, disease genes, identification, microarray, nonsense mediated mRNA decay, RNA interference, SNAREs.